The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Stephen Opat, Alessandra Tedeschi, Kim Linton, Pamela McKay, Bei Hu, Henry Chan, Jie Jin, Magdalena Sobieraj-Teague, Pier Luigi Zinzani, Morton Coleman, Catherine Thieblemont, Peter Browett, Xiaoyan Ke, Mingyuan Sun, Robert Marcus, Craig A Portell, Kirit Ardeshna, Fontanet Bijou, Patricia Walker, Eliza A Hawkes, Sally Mapp, Shir-Jing Ho, Dipti Talaulikar, Ke-Shu Zhou, Melannie Co, Xiaotong Li, Wenxiao Zhou, Massimo Cappellini, Chris Tankersley, Jane Huang, Judith Trotman

TLDR

  • Zanubrutinib is a new drug that can help treat a type of cancer called marginal zone lymphoma (MZL). It works by targeting a protein called Bruton tyrosine kinase (BTK), which is important for the growth and survival of cancer cells. In a study, zanubrutinib was given to patients with MZL who had already tried other treatments and were not responding well. The study found that zanubrutinib was effective in treating the cancer, with many patients experiencing a complete response (CR) or a significant reduction in the size of their tumors. The drug was also well tolerated, with most side effects being mild. Overall, the study suggests that zanubrutinib could be a promising new treatment option for patients with MZL.

Abstract

Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111-214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Overview

  • The study evaluates the efficacy and safety of zanubrutinib in patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL).
  • The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Comparative Analysis & Findings

  • Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL. The IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Implications and Future Directions

  • The study highlights the potential of zanubrutinib as a treatment option for patients with R/R MZL. The high ORR and CR rate, along with the favorable safety profile, suggest that zanubrutinib may be a promising alternative to traditional chemotherapy-based treatments. Future studies should further evaluate the long-term efficacy and safety of zanubrutinib in patients with R/R MZL, as well as its potential for use in earlier-stage disease. Additionally, studies should explore the combination of zanubrutinib with other targeted therapies or immunotherapies to enhance its efficacy and improve patient outcomes.
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